Abstract 449: Expression of Type IIA Secretory Phospholipase A2 (sPLA2) Inhibits Cholesteryl Ester Transfer Protein (CETP) Activity in Transgenic Mice
High circulating levels of group IIA secretory phospholipase (sPLA2-IIA) activity as well as mass are independent cardiovascular risk factors. Therefore, inhibition of sPLA2-IIA may be a target for the treatment of atherosclerotic cardiovascular disease (CVD). The present study evaluated the effects of sPLA2-IIA inhibition with varespladib acid in a novel mouse model, human apolipoprotein B/human cholesteryl ester transfer protein (CETP)/human sPLA2-IIA triple transgenic mice (TTT) fed a Western-type diet. sPLA2-IIA expression increased atherosclerotic lesion formation in TTT compared with human apolipoprotein B/human CETP double transgenic mice (p<0.01). varespladib acid effectively inhibited plasma sPLA2-IIA activity. Surprisingly, however, administration of varespladib acid to TTT had no impact on atherosclerosis, which could be attributed to a pro-atherogenic plasma lipoprotein profile that appears in response to sPLA2-IIA inhibition due to increased plasma CETP activity. In the TTT model sPLA2-IIA decreased CETP activity by reducing the acceptor properties of sPLA2-IIA-modified VLDL specifically due to a significantly lower apoE content. Increasing VLDL apoE content by means of adenovirus-mediated gene transfer in sPLA2-IIA transgenic mice restored the acceptor properties for CETP. In conclusion, these data show that in a humanized triple transgenic mouse model with hypercholesterolemia, sPLA2-IIA inhibition increases CETP activity via increasing the VLDL apoE content resulting in a pro-atherogenic lipoprotein profile.
- © 2013 by American Heart Association, Inc.